Abstract
In cells, thymidylate synthases provide the only de novo source of 2′-deoxythymidine-5′-monophosphate (dTMP), required for DNA synthesis. The activity of these enzymes is pivotal for cell survival and proliferation. Two main families of thymidylate synthases have been identified in bacteria, folate-dependent thymidylate synthase (TS) and flavin-dependent TS (FDTS). TS and FDTS are highly divergent enzymes, characterized by exclusive catalytic mechanisms, involving different sets of cofactors. TS and FDTS mechanisms of action have been recently revised, providing new perspectives for the development of antibacterial drugs targeting these enzymes. Nonetheless, some catalytic details still remain elusive. For bacterial TSs, half-site reactivity is still an open debate and the recent evidences are somehow controversial. Furthermore, different behaviors have been identified among bacterial TSs, compromising the definition of common mechanisms. Moreover, the redox reaction responsible for the regeneration of reduced flavin in FDTSs is not completely clarified. This review describes the recent advances in the structural and functional characterization of bacterial TSs and FDTSs and the current understanding of their mechanisms of action. Furthermore, the recent progresses in the development of inhibitors targeting TS and FDTS in human pathogenic bacteria are summarized.
Highlights
Thymidylate synthase is a class of methyltransferase enzymes required for de novo20 -deoxythymidine-50 -monophosphate synthesis
This review describes the recent advances in the structural and functional characterization of bacterial thymidylate synthase (TS) and flavin-dependent TS (FDTS) and the current understanding of their mechanisms of action
The structural characterization of FDTSs from human pathogenic bacteria is limited to the enzymes from Mycobacterium tuberculosis (MtbFDTS; Protein Data Bank (PDB) id 2AF6 [42]) and Helicobacter pylori
Summary
Thymidylate synthase is a class of methyltransferase enzymes required for de novo. 20 -deoxythymidine-50 -monophosphate (dTMP) synthesis. The major challenges are the identification of new microbial targets and the development of effective antibiotic therapies able to treat resistant infections For this purpose, FDTS represents a promising target for the of new antibiotics, since it has no counterpart enzyme in the human 2host. For this purpose, FDTS represents a promising target for the development of new antibiotics, since it has no counterpart enzyme in the human host [13,14]. This review is aimed to summarize the current understanding of structure and function of bTSs and FDTSs and the recent progresses in the development of inhibitors targeting these enzymes in human pathogenic bacteria
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.